Process for synthesizing carbapenem using raney nickel

Abstract

Convenient method for obtaining carbapenem by hydrogenation with Raney Nickel, as an alternative to the known catalytic hydrogenation conducted under hydrogen overpressure in the presence of Palladium, starting from corresponding protected intermediates such as p-nitrobenzylesters and with optional suitable protections of any primary and secondary amino functions structurally present.

1 . A process for synthesizing carbapenem of formula (I): 
     
       
         
         
             
             
         
       
       or of a pharmaceutically acceptable salified, prodrug or hydrated form thereof, in which R1 is chosen from the group consisting of H and C1-C6 alkyls, X is chosen from the group consisting of —CH 2 —CH 2 —NH—CH═NH, —CH 2 —CH 2 —NH 2 , 
     
     
       
         
         
             
             
         
       
       where Y is chosen from the group consisting of 
     
     
       
         
         
             
             
         
       
       in which f is equal to 0 or 1, while m and n, whole numbers different from 0, are independently chosen to form an azaheterocycle from 3 to 6 carbon atoms, —H, —CN, hydroxy(C1-C6)alkyls, carbamoyloxy, —OH, substituted or non-substituted linear or branched chain C1-C6 alkyls, C2-C6 alkenyls, C3-C6 cycloalkyls, —R8NHSO 2 R6 in which R8 is a C1-C3 alkyl chain, —NHR9-SO 2 —R6 in which R9 and R6 are independently chosen from the group consisting of hydrogen or C1-C6 alkyls, —N(R7) 2  where R7 is a C1-C3 alkyl chain, 
     
     
       
         
         
             
             
         
       
       in which X1 is chosen from the group consisting of NH and O while R20 and R21, when independently selected, are chosen from the group comprising H, C1-C5 alkyls, C3-C5 alkenyls, aryl, substituted aryl, substituted aryl carboxy, aralkyls which can be variously substituted with C1-C3 alkyl substituents or monosubstituted with a C1-C5 alkyl or a pyridyl, or R20 and R21, when linked together, are chosen from the group comprising alkylene chains, alkylene chains bridged by a nitrogen atom substituted by a C2-C3 alkyl chain to form a diazaheterocycle, (C1-C5)alkyls-L-G-(C1-C5)alkyls, —NH, —N(L) in which G is O, S, while L are alkyls or alkenyls optionally substituted by from 1 to 3 substituents chosen from the group consisting of 
     
     
       
         
         
             
             
         
       
       in which X 2  è chosen from the group consisting of O or NH while R3 è chosen from the group of the following azaheterocycles 
     
     
       
         
         
             
             
         
       
       and amines, optionally substituted with 
     
     
       
         
         
             
             
         
       
       in which R4 and R5 are independently chosen from the group consisting of H, hydroxy(C1-C6)alkyls, CN, amino, carbamoyl, carbamoyl(C1-C6)alkyls, cyano(C1-C6)alkyls, mono- or di-(C1-C6)alkylcarbamoyl, carbamoyloxy, ureide, amino(C1-C6)alkyl, carbamoyloxy(C1-C6)alkyls, mono- or di-(C1-C6)alkylcarbamoyl-(C1-C6)alkyls, ureide(C1-C6)alkyls, starting from the corresponding intermediates of formula (II) 
     
     
       
         
         
             
             
         
       
       in which X and R1 have the meanings indicated for the compounds of formula (I), where any primary and secondary amino functions present can be optionally protected with suitable protective groups, by deprotecting the p-nitrobenzyl ester of the intermediate (II) with Raney Nickel in water miscible or immiscible protic or aprotic organic solvents, in the presence of hydrogen which may even have been simply preabsorbed on the Raney Nickel. 
     
   
   
       2 . A process as claimed in  claim 1 , wherein said optional suitable protective groups, which may be present for at least one of the primary and secondary functions of the intermediates of formulas (II), are chosen from the group consisting of p-nitrobenzyloxycarbonyl and allyloxycarbonyl. 
   
   
       3 . A process as claimed in  claim 1  for obtaining meropenem and ertapenem, compounds comprised in formula (I), of formula (III) and (IV) respectively